Nanofiltration (NF) membranes have retention characteristics in the range between ultrafiltration and reverse osmosis. Nanofiltration membranes are used to remove multivalent ions and small organic molecules in the molecular weight range of approximately 200-1000 Daltons. The ability to remove small organic molecules has led to much interest for applications in pharmaceutical industries. In particular, there is an interest in operating in organic solvent streams to separate small molecules such as synthetic antibiotics and peptides from organic solutions. In these types of applications, a high permeability is required for economical operation.
Polar organic solvents, such as dipolar aprotic solvents, particularly solvents such as N-methyl pyrrolidone (NMP), dimethylacetamide (DMAC), and dimethylsulfoxide (DMSO) are used as solvents or media for chemical reactions to make pharmaceuticals and agrochemicals (for example, pyrethroid insecticides) industry. These powerful solvents will cause severe damage to commonly used polymeric membrane titters made from polysulfone, polyethersulfone, polyacrylonitrile or polyvinylidene fluoride polymers.
In many applications, it would be useful for the membrane to operate with aqueous mixtures of solvents or with both aqueous solutions and solvent based solutions in series. For such uses, hydrophobic membranes are not useful as they have very low permeabilities for aqueous solutions. Low aqueous permeability in hydrophobic NF membranes is shown in Advances in Solvent-Resistant Nanofiltration Membranes, Ann. N.Y. Acad. Sci. 984 159-177 2003.
A typical use for these membranes is to concentrate products in organic or aqueous/organic solutions prior to a crystallization step. In other applications, process operators are able to remove low molecular weight impurities and salts by diafiltration, which cannot be done with an evaporation step. Operators are also able to exchange solvents during this type of filtration process. Nanofiltration of organic solutions can replace vacuum flash evaporators or rotovaps, providing a lower capital cost process.
In the processing of peptides and other low molecular weight organic solutes, the capacity of the membrane to be non-binding is an important attribute. Solutes bound to the membrane lower permeability and reduce yield by irreversibly holding solute. Cellulose is well-known as having a very low binding surface for such molecules, whereas hydrophobic and the typical polyamide NF membranes are known to be highly binding.
Cellulose is solvent stable, being soluble only in strong solvents such as carbon disulfide and solutions of dimethylacetamide with lithium chloride. When crosslinked, cellulose has even less tendency to swell and is therefore a good candidate for a solvent stable NF membrane. To date no commercial membrane has been produced because of the difficulties involved in making a porous NF membrane from cellulose.
Rendall, in U.S. Pat. No. 3,864,289, describes a process for the preparation of a cellulosic semipermeable membrane from a formulation containing a cellulosic membrane material, a cellulosic crosslinking agent and a blocking agent. The use of a “blocking agent” is undesirable because it adds unnecessary complexity to the process and an additional chemical change to the nature of the membrane material. Such blocking agents can also add to undesirable extractable material which can contaminate the purified permeate.
Wan, in U.S. Pat. No. 4,853,129, describes regenerated cellulose membranes for separating organic liquids, such as ketone dewaxing solvents from dewaxed oil. Reacting regenerated cellulose membranes with a bifunctional reagent results in improvement of the membrane's selectivity in organic liquid separations applications. Wan states that the process also serves to reduce the hydrophilicity of the membranes, and that by use of the crosslinking agents no unreacted hydroxy groups are left after reaction, nor are any hydroxy groups introduced by the crosslinking agent. Such membranes would not be suitable fur use with water solutions, or solutions with appreciable amounts of water.
The membranes in the Wan patent have rejection values for oils of molecular weights in the range of from about 300-600 Daltons of 55%-90%. (Molecular weight data from concurrent U.S. Pat. No. 4,510,047.) These rejections are not suitable for the high value added products of pharmaceutical manufacturers.
Beer et al, in U.S. Pat. No. 5,739,316, claims as process for making a cross-linked cellulose hydrate ultrafiltration membrane comprising contacting a cellulose hydrate membrane with an aqueous alkaline solution of a water soluble diepoxide. Besides being limited to water soluble diepoxides. Beer teaches away from the use of organic solvents in the reactions as being technically difficult and expensive. Moreover, Beer states as an objective of his invention a process that does not modify the high flux of the membrane. This means that the membranes so produced would not have increased rejection from the initial ultrafiltration membrane.
Charkoudian, in U.S. patent application Ser. Nos. 11/199,491 and 10/414,988 teaches crosslinked and crosslinked and charged cellulose ultrafiltration membranes that retain the ultrafiltration structure of the membranes.
U.S. Pat. No. 6,113,794 describes a nanofiltration composite membrane comprising a substrate ultrafiltration membrane formed from non-cross-linked ethylenically unsaturated nitrile polymer, and a porous coating of a cross-linked hydrophilic polymer having a molecular weight of 20,000 to 2,000,000 and containing reactive functional groups, formed from an aqueous solution of the polymer containing 1.5-2.5% w/w of the polymer. The patent is directed to chitosan coated membranes that are completely dried before being crosslinked. This will produce a dense film rather than a porous membrane.
The U.S. Pat. No. 6,113,794 patent cannot be used with dipolar aprotic solvents such as N-methyl pyrrolidone or dimethylacetamide because such solvents will dissolve the support layer and destroy the composite membrane.
Guo et al in Chinese Chemical Letters, Vol 5, (10) pp 869-872 1994 reports on crosslinking large pore cellulose membranes with DMSO aqueous alkaline solutions of epoxyl propane chloride (epichlorohydrin). These membranes were used for affinity separations. Such large pore membranes would not be suitable for small molecule separations, and there is no teaching that the method could be used to make ultrafiltration or NF membranes.
Several patent applications and articles have been published by authors primarily associated with GKSS Research Center. These all appear to be based on the same technology. This method (WO 97/20622) coats a substrate membrane with a low solids solution of cellulose-hydroxyether, such as hydroxyethylcellulose or hydroxypropyl cellulose, and then crosslinks the coating with aldehyde, preferably a dialdehyde to the point of water insolubility. In an article in JAOCS Vol 76#1, pp 83-87 1999, Zwijnenberg et al report on nanofiltration of vegetable oils in acetone using composite membranes with a “cellulose-type top-layer.” In Membrane Technology #107 pp 5-8 1999, Ebert et al report on nanofiltration of vegetable oils in solvents with “cellulose-type” membranes in which the performance of the cellulose type membranes is influenced by the crosslinking conditions. Cellulose hydroxyethers are a different class of material from regenerated cellulose, as can be sea by the referenced authors describing the material as cellulose-like. Cellulose hydroxyethers are water soluble and can be expected to behave differently from regenerated cellulose membranes in operation. The membranes made from cellulose hydroxyethers are formed from thin dense layers and will have a different structure than the regenerated cellulose made by phase separation methods.
The inventors of the present invention have found that by using a porous ultrafiltration membrane as a precursor, and carefully controlling reaction conditions so as to maintain sufficient hydrophilic nature of the membrane, they can produce a solvent stable cellulose nanofiltration membrane capable of operating at satisfactory flux in aqueous solutions, including aqueous-solvent mixtures or blends, which is also low binding to organic biomaterials.